17-alkylsulfonyl and 17-alkylsulfinyl estratrien-3-ols



United States Patent 17 -ALKYLSULFONYL AND 17 -ALKYLSULFINYLESTRATRIEN-S-OLS Raymond M. Dodson, Park Ridge, and Paul B. Sollman,Skokie, Ill., assignors to G. D. Searle & Co., Chicago, Ill., acorporation of Delaware No Drawing. Application June 23, 1958 Serial No.743,981

Claims. (Cl. 260397.5)

The present invention relates to a new class of thiosteroids. It isconcerned in part with those derivatives of 1,3,5 ()-estratrien-3-ol,its ethers and esters which are substituted at the 17-position byalkylsulfinyl or alkylsulfonyl groups. It is also concerned with16-dehydro derivatives of these compounds. Accordingly, the compounds ofthis invention include the estratriene derivatives of the structuralformula CHa (lower)alkyl and the estratetraene derivatives of thestructural formula (lower)alky1 in which R can represent hydrogen,(lower) alkyl or acyl and n can represent the integers 1 or 2. The term(lower)alkyl can represent methyl, ethyl, propyl, butyl, amyl, hexyl,heptyl, octyl and branched-chain isomers thereof. Acyl radicalscomprehended Within the term R are preferably the acyl radicals ofhydrocarbon carboxylic acids having fewer than nine carbon atoms. Suchacyl radicals can be lower alkanoyl radicals, such as formyl, acetyl,propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl, andbranched-chain isomers thereof. Other suitable acyl radicals are thosewhich are cyclic or partially-cyclic in structure. Representative ofsuch acyl radicals are cyclopentanecarbonyl, cyclohexanecarbonyl,cyclopentaneacetyl, cyclopentanepropionyl, cyclohexaneacetyl, benzoyl,methylbenzoyl, phenylacetyl, and homologs and isomers of the foregoing.

r6 ice I having the partial formula and in which theoppositeconfigurations of the sulfoxide oxygen are represented byarbitrary means. The invention comprehends compounds in which the sidechain attached to position 17 are in the ,8 as Well as the aconfigurations.

It is further to be noted that for purposes of convenience, the sulfonesand 'sulfoxides are represented herein by their classical covalent bondstructures, whereas the modern view, less easily representable, is thatthese compounds are resonance hybrids of the covalent double bondstructure and the semipolar bond structure. It will be obvious that lackof agreement among those skilled in the art as to the precise nature ofthe valence bonds of sulfones and sulfoxides does not in any way limitthe useful applications of the compounds of this invention.

Among the starting materials suitable for the manufacture of thecompounds of this invention are the 17- alkylthio substitution productsof 1,3,5 (ND-estratrien- 3-ol, their 16-dehydro derivatives and ethersand esters thereof.

The compounds of the invention are prepared by oxidizing a17-alkylthio-1,3,5(10)-estratrien-3-ol or desired derivative thereof, tothe corresponding sulfoxide or sulfone by treatment with a peroxy acid,such as permaterial are isolated when the oxidation reaction is run inthis manner. When a solution of the desired starting material is treatedwith approximately two molecular equivalents of perbenzoic acid, theprincipal product is p the corresponding sulfone.

Esters of the 3-hydroxyl group can be made by esterification of theproduct resulting from the oxidation step or alternatively the step ofesterification can be carried out prior to the step of oxidation.Esterification is accomplished by treatment with an appropriate acidanhydride or acid chloride and pyridine.

The compounds of this invention have useful pharmacological properties.More specifically, they exhibit an inhibitory effect on the Coxsackievirus. They antagonize the spread of virus infection followingadministration of cortisone.

This invention will appear more fully'from the examples which follow.These examples are set forth by way of illustration only, and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples quantities areexpressed in parts by weight and parts by volume which bear the samerelation one to another as kilograms to liters. Temperatures areexpressed in degrees centigrade C.).

Example 1 To a stirred solution of 12.2 parts by weight of3-hydroxy-l,3,5(l)-estratriene-l7,8-thiol and 4.82 parts bytrien-3-ol,melting point 143; specific rotation +61.7

in chloroform solution.

To a solution of 3.02 parts by weight ofIDS-methylthio-1,3,5(10)-estratrien-3-ol in 200 parts by volume ofbenzene is added a benzene soluton of 1.03 molar equivalents ofperbenzoic acid (62 parts by volume of 0.166 molar perbenzoic acid). Aninsoluble product begins to precipitate after about one half of theperbenzoic acid solution is added. The reaction mixture is allowed tostand for 30 minutes following the addition of the perhenzoic acidsolution and then the solid reaction product is recovered by filtration.Recrystallization of-the reaction product from a mixture of dimethylformamide, benzene and Skellysolve B yields l7fi-methylsnlfinyl-1,3,5(10)- estratrien-3-ol having the formula which melts at 287-290(decomposition).

Example 2 To a solution of'2.75 parts by weight of17p-methylthio-1,3,5(l0)-estratrien-3-ol in 50 parts by volume of aceticacid is added a solution of 2 molar equivalents of perbenzoic acid inbenzene. The reaction mixture is diluted with 200 parts by volume ofwater, filtered and the solid reaction product thus recovered is dried.After two crystallizations from aqueous acetone and one crystallizationfrom methanol the reaction product; 1713-methylsul 4 fonyl-l,3,5(l0)-estratrien-3-ol melts at 298-300" (decomposition). The product has theformula C 'o ild" Two and nine-tenths parts by weight of methyliodide isadded to a solution of 2.7 parts by weight of 3-hydroxy-1,3,5(10.)-estratriene-17-thione dissolved in a solution of 1.1 parts byweight of sodium methoxide in parts by volume of methanol. Afterstirring for-5 minutes, the reaction mixture is diluted with 200 partsby volume of water followed by the addition of 10 parts by volume ofacetic acid whereupon a heavy precipitate separates. The insolubleproduct is collected on a filter and crystallized from mixtures ofacetone and petroleum ether to yield 17-methylthio-1,3,'5 1 0),16-estratetraen-3-ol which melts at l42143 and has a specific rotationof +85.7 in chloroform solution.

To a solution of 5.1 partsby weight of17-methylthiol,3,5(10),16-estratetraen-3-ol ,dissolved in 250 parts byvolume of benzene is added a solution of 1.04 molar equivalents ofperbenzoic acid in benzene. The reaction mixture is stirred for one andone-half hours following the addition of the perbenzoic acid solution,filtered and the solid reaction product thus obtained crystallized twicefrom acetone to yield 17-methylsulfinyl-1,3,5( 10),16-estratetraen-3-olwhich has a melting point of 267268 and a specific rotation of +27.8 inchloroform. The product has the formula A solution of 0.1 part by weightof l7-methylsulfinyl- 1,3,5(10),l6-estratetraen-3-ol in 3 parts byvolume of pyridine and 3 parts .by volume of propionic anhydride isallowed to stand at room temperature for. 24 hours. The solution ispoured into 100 parts by volume of ice water and the oilyphase thusprecipitated is stirred for one hour. The mixture is extracted withethyl acetate, the extract washed with water, dried over anhydroussodium sulfate and concentrated to dryness. The oily residue isdissolved in a mixture of isopropyl ether and hexane and the solutionchilled'at 70. The supernatant liquid is decantedto leavel7methylsulfinyl-l,3,5(l0),16estratetraen-S-ol propionate as an oilwhich exhibits absorp- 5 tion maxima in the infrared spectrum at 5.68,6.66, 6.81, 7.01, 7.25, 7.36.8.64, 9.53 and 9.96 microns.

Example 4 17-methylsulfonyl-1,3,5 (10) ,16-estratetraen-3-ol having a.

melting point of 229-231 and a specific rotation of +60 in chloroform.The product has the formula Example A solution prepared from 9.7 partsof estrone acetate,-

8.2 parts ofbenzyl mercaptan, 37 parts of acetic acid and 1 part ofp-toluenesulfonic acid monohydrate is allowed to stand at about 25 for20 hours. Sodium acetate (3 parts) and ice (100 parts) are added,causing the precipitation of an oily product. The suspension is madeslightly basic with sodium carbonate and extracted with several portionsof ether. The combined ether extract is washed with water, dried oversodium sulfate and filtered. The residue obtained by concentration ofthe filtrate is dissolved in benzene and poured on a chromatographycolumn prepared from 190 parts of silica. Elution of the column withbenzene and then with a volume percent solution of ethyl acetate inbenzene affords first a small amount of benzyl mercaptan. Furtherelution with a 10 volume percent solution of ethyl acetate in benzeneaffords an odorless, viscous oil which is the crude dibenzylmercaptoleof estrone acetate. This compound has the structural formula CHzSCHzCoHg I:'"'SCH2OGHE CfiaC 0 o A solution of 11.3 parts of the crudedibenzylmercaptole of estrone acetate in 35 parts of ether is slowlyadded to a solution of 20 parts of sodium in 330 parts of liquidammonia. The reaction mixture is stirred for 2 hours, after which timean additional 280 parts of ether is added. There is then cautiouslyadded 120 parts of ethanol followed by(after reaction of the sodium iscomplete) 300 parts of water. The reaction mixture is extracted withether and this ethereal extract, which contains bibenzyl, is discarded.The aqueous solution or suspension is made acidic by the addition ofammonium chloride and extracted with ether. The residue obtained byconcentration of this ethereal extract is crystallized from a mixture ofbenzene and'petroleum ether to afford yellow crystals of3-hydroxy-1,3,5(10)-estratriene-17-thione. After further purification byrecrystallization from benzene, this 6. compound melts at about 212-213.It gives a pink solution in benzene. This compound has the structuralformula 3-hydroxy-1,3,5(10)-estratriene-17-thione (2.7 parts) isdissolved in a solution of 1.4 parts of sodium ethoxi-de in parts ofethanol. Ethyl iodide (3.1 parts) is added, and after 5 minutes ofreaction time the mixture is diluted with 200 parts of water. Upon theaddition of 10 parts of acetic acid, a heavy precipitate separates. Thisinsoluble product is collected on a filter and purified bycrystallizations from mixtures of acetone and petroleum ether. Thiscompound is l7-ethylthio-1,3,5(10),16-estratetraen-3-ol which has thestructural formula SCHzCHa When a solution of 3 parts of this compoundin 160 parts of ethanol is treated over a period of 20 minutes with atotal of 20 parts of a 10% sodium hydroxide solution and a total of 5parts of diethyl sulfate, added alternately and in divided portions, andthe reaction mixture is diluted with several times its volume of water,the insoluble product formed is3-ethoxy-17-ethylthio-1,3,5(10),16-estratetraene. For purification, asolution of this product in petroleum ether is washed with severalportions of dilute sodium hydroxide solution and with water, followingwhich it is rendered anhydrous and concentrated to a small volume forcrystallization.

To a solution of 3.5 parts by weight of 3-ethoxy-17B- ethylthio-1,3,5(10),16-estratetraene in parts by volume of acetic acid is added slowlya. solution of 1.03 molar equivalents of perbenzoic acid in about 60parts by volume of benzene. The reaction mixture is stirred for anadditional 30 minutes, diluted with 300 parts by volume of water, 300parts by volume of ethyl acetate and exhibits absorption maxima in theinfrared spectrum at 6.2, 6.65, 6.8 and 9.6 microns Example 6 To asolution of 2.7 parts by weight of 3-hydroxy- 1,3,5 (10)-estratriene-l7-thione, 1.1 parts by weight of sodium methoxide and 100parts by volume of methanol is added 2.9 parts by Weight of butyliodide. The mixture is stirred for 20 minutes, diluted with 200 parts byvolume of water and then 10 parts by volume of acetic acid added. Theheavy precipitate which is formed is collected on a filter and purifiedby crystallizations from mixtures of acetone and petroleum ether to give17- butylthio-1,3,5(10),16-estratetraen-3-ol.

A solution of 3.4 parts by weight of 17-butylthio-1,3,5(l0),16-estratetraen-3-ol in 200 parts by volume of methanol is treatedover a period of 20 minutes with a total of 20 parts by volume of a 10%sodium hydroxide solution and a total of 5 parts by weight of dimethylsulfate, added alternately and in divided portions, and the reactionmixture is diluted with several times its volume of water, the insolubleproduct formed is 3-rncthoXy-l7- butylthio-1,3,5( 10) ,l6-estratetraene.

To a solution of 3.6 parts by weight of 3-methoxy17-butylthio-l,3,5(l),l6-estratetraene in 100 parts by volume of aceticacid is added 2.03 molar equivalents of perbenzoic acid dissolved inbenzene. The reaction mixture is stirred for an additional 30 minutesand 300 parts by volume of water, 300 parts by volume of ethyl acetateand 300 parts by volume of ether is added. The aqueous layer isseparated, washed with 200 parts by volume of 1:1 ethyl acetate-etherand the combined organic solvent portions washed with water, then withsodium bicarbonate solution to neutrality and again with water and driedover anhydrous sodium sulfate. The solvents are removed and the solidresidue crystallized from ethanol-water to yield 17-butylsulfonyl 3methoxy1,3,5(10),16-estratetraene which'has the formula GHaO Example 7 Asolution of sodium hydrosulfide is prepared by passing a stream ofhydrogen sulfide gas through a mixture of 110 parts of ethylene glycolmonoethyl ether and 7.5 parts of sodium methoxide, until substantiallyall of the sodium methoxide is consumed, as evidenced by the completionof the exothermic reaction. About 1 hour is a convenient period of timefor this reaction.

This solution of sodium hydrosulfide is mixed with 4.2 parts of17B-(p-toluenesulfonoxy)-1,3,5(10)-estratrien-3-ol and heated underreflux for 3 hours. The reaction mixture is then poured into 600 partsof water, acidified with 18 parts of concentrated hydrochloric acid andextracted with several portions of a mixture of ether and benzene. Thecombined organic extract is washed with water and concentrated todryness. A solution of the residue in benzene is poured on achromatography column prepared from 100 parts of silica. An oily product(about 1.6 parts) obtained by elution of the column with a volumepercent solution of ethyl acetate in benzene is dissolved in 210 partsof ether, and the ethereal solution is extracted with a total of 1000parts of 5% sodium hydroxide solution, in several portions. The aqueous,alkaline extract is acidified'with dilute hydrochloric acid andextracted with several portions oi ether,

This combined ethereal extract is washed with water and concentrated todryness. The oily residue obtained in this manner is crystallized froma. mixture of ether and petroleum ether. Further purification byrepeated recrystallization from mixtures of benzene and petroleum etheror by a second chromatographic fractionation on'a silica gel columnalfords purified 3-hydroxy-1,3,5(10) estratriene-lh-thiol melting atabout l35136.5 C.

To a stirred solution of 12.2 parts by weight of 3-hydroxy-1,3,5(10)-estratriene-17a-thiol and 4.82 parts by Weight ofsodium methoxide in 300 parts by volume of methanol is added over aperiod of 5-10 minutes a solution of 6.64 parts by weight of methyliodide in 50 parts by volume of methanol. The temperature is maintainedin the range of about 25-35 during the period of additionand for about 5minutes thereafter, following which 1300 parts by volume of water and 21parts by volume of acetic acid are added. The precipitated product iscollected on a filter, Washed with water and recrystallized from benzeneto yield 17a-methylthio-1,3,5(10)-estratrien-3-ol.

To a solution of 3.02 parts by weight of17a-methylthio-1,3,5(10)-estratrien-3-ol in 200 parts by volume ofbenzene is added a benzene solution of 1.03 molar equivalents ofperbenzoic acid (62 parts by volume of 0.166 molar perbenzoic acid). Aninsoluble product begins to precipitate after about one half of theperbenzoic acid solution is added. The reaction mixture is allowed tostand for 30 minutes following the addition of the perbenzoic acidsolution and then the solid reaction product is recovered by filtration.Recrystallization of the reaction product from a mixture of dimethylformamide, benzene and Skellysolve B yields 17a-methy1-sulfinyl-1,3,5(l0)-estratrien-3-ol which has the formula Example 8 A solution ofsodium hydrosulfide is prepared by passing a stream of hydrogen sulfidegas through a mixture of 550 parts of ethylene glycol monoethyl etherand 50 parts of sodium methoxide, until substantially all of the sodiummethoxide is consumed, as evidenced by the completion of the exothermicreaction. About 1 hour is a convenient period of time; for thisreaction.

To this solution is added 20 parts of3-methoxy-17flmethanesulfonoxy-1,3,5 (10)-estratriene, and the mixtureis heated under reflux for three hours. It is then poured into 2000parts of water, and the resulting mixture is acidified with parts ofconcentrated hydrochloric acid, and extracted with a total of 900 partsof ethyl acetate in 3 portions. The ethyl acetate solution is washedsuccessively with water, with sodium bicarbonate solution, and withsaturated sodium chloride solution, following which it is renderedanhydrous, filtered, and distilled to dryness. A solution of the residuein the minimum quantity of a 20 volume percent solution of henzene inpetroleum ether is poured onto a chromatography column prepared from 400parts of silica, and the column is eluted with further quantities of thesame solvent mixture, followed by mixtures of benzene and petroleumether containing gradually increasing proportions of benzene. Thedesired compound, corresponding to a weight peak in the elution curve,is eluted at a satisfactory rate with a 50 volume percent solution ofbenzene in petroleum ether. Upon crystallizations from aqueous methanoland from aqueous ethanol these eluate residues afiord3-methoxy-1,3,5(10)-estratriene-l7a-thiol melting at about 77-82 C. andexhibiting a specific rotation of about +313 in chloroform solution.

To a stirred solution of 12.2 parts of 3-methoxy-1,3,()-estratriene-17a-thiol and 4.75 parts of sodium methoxide in 240 partsof methanol is added over a period of 5-10 minutes a solution of 6.5parts of methyl iodide in 40 parts of methanol. The temperature ismaintained in the range of about 2535 C. during the period of additionand for about 5 minutes thereafter, following which 1300 parts of waterand 21 parts of acetic acid are added. The precipitated product iscollected on a filter and washed with water. Upon recrystallization frombenzene there is obtained3-methoxy-l7u-methylthio-1,3,5(10)-estratriene.

To a solution of 2.75 parts by weight of 3-methoxy-17a-methylthio-l,3,5(10)-estratriene in 50 parts by volume of aceticacid is added a solution of 2 molar equivalents of perbenzoic acid inbenzene. The reaction mixture is diluted with 200 parts by volume ofwater, filtered and the solid reaction product thus recovered is dried.Recrystallization from aqueous acetone and then from methanol yields3-methoxy-17u-methylsulfonyl-1,3,5(10)- estratriene which has theformula O CH:

CHaO

10 What is claimed is: 1. A member of the class consisting of compoundsof the structural formula CH: 5 (lower)alkyl and the compounds of thestructural formula (lower)alkyl

1. A MEMBER OF THE CLASS CONSISTING OF COMPOUNDS OF THE STRUCTURALFORMULA